Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Abstract The durable clinical efficacy of immune checkpoint inhibitors in a variety of cancers has demonstrated the tremendous potential of tumor immunotherapy. However, current approaches are limited to immunogenic tumors that acquire adaptive resistance. Interleukin-2 (IL-2) immunotherapy can result in remarkable long-term responses in some cancer patients by stimulating the immune response to kill tumor cells. However, current rIL-2 therapy is limited to highly selected patients due to its requirements for high and frequent dosing, which results in severe side effects. Moreover, rIL-2 also activates CD4+ regulatory T cells, which suppress the immune response. To ameliorate the liabilities of the current rIL-2 drug, we have designed a long-acting IL-2 analog that selectively preserves immune response activation (CD8+ T, NK cells), without activating regulatory T cells and endothelial cells; thereby, minimizing immune suppression and vascular leak syndrome. We also propose to optimize combination rIL2 analog treatment plus checkpoint therapy in order to safely and effectively kill tumor cells by simultaneously activating anti-tumor pathways of the immune system and removing inhibitory mechanisms. In this study, the Specific Aim is to use a syngeneic B16F10 mouse model to determine whether the combination of the proprietary IL-2 analog with checkpoint therapy (PD-1 blockade) is more effective in eradicating tumors without increasing side effects. Our long-term goal is to develop the proprietary IL-2 analog as a safe immunotherapy to cure cancer or extend survival of patients.